RESUMO
Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.
Assuntos
Estudo de Associação Genômica Ampla , Genoma , Humanos , Estudo de Associação Genômica Ampla/métodos , Sequenciamento Completo do Genoma/métodos , Fenótipo , Variação GenéticaRESUMO
Previous studies suggest that gyrification is associated with superior cognitive abilities in humans, but the strength of this relationship remains unclear. Here, in two samples of related individuals (total N = 2882), we calculated an index of local gyrification (LGI) at thousands of cortical surface points using structural brain images and an index of general cognitive ability (g) using performance on cognitive tests. Replicating previous studies, we found that phenotypic and genetic LGI-g correlations were positive and statistically significant in many cortical regions. However, all LGI-g correlations in both samples were extremely weak, regardless of whether they were significant or nonsignificant. For example, the median phenotypic LGI-g correlation was 0.05 in one sample and 0.10 in the other. These correlations were even weaker after adjusting for confounding neuroanatomical variables (intracranial volume and local cortical surface area). Furthermore, when all LGIs were considered together, at least 89% of the phenotypic variance of g remained unaccounted for. We conclude that the association between LGI and g is too weak to have profound implications for our understanding of the neurobiology of intelligence. This study highlights potential issues when focusing heavily on statistical significance rather than effect sizes in large-scale observational neuroimaging studies.
Assuntos
Córtex Cerebral/diagnóstico por imagem , Cognição/fisiologia , Inteligência/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebral/anatomia & histologia , Feminino , Humanos , Inteligência/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto JovemRESUMO
AIMS/HYPOTHESIS: Type 2 diabetes is associated with cognitive impairments, but it is unclear whether common genetic factors influence both type 2 diabetes risk and cognition. METHODS: Using data from 1892 Mexican-American individuals from extended pedigrees, including 402 with type 2 diabetes, we examined possible pleiotropy between type 2 diabetes and cognitive functioning, as measured by a comprehensive neuropsychological test battery. RESULTS: Negative phenotypic correlations (ρp) were observed between type 2 diabetes and measures of attention (Continuous Performance Test [CPT d']: ρp = -0.143, p = 0.001), verbal memory (California Verbal Learning Test [CVLT] recall: ρp = -0.111, p = 0.004) and face memory (Penn Face Memory Test [PFMT]: ρp = -0.127, p = 0.002; PFMT Delayed: ρp = -0.148, p = 2 × 10-4), replicating findings of cognitive impairment in type 2 diabetes. Negative genetic correlations (ρg) were also observed between type 2 diabetes and measures of attention (CPT d': ρg = -0.401, p = 0.001), working memory (digit span backward test: ρg = -0.380, p = 0.005), and face memory (PFMT: ρg = -0.476, p = 2 × 10-4; PFMT Delayed: ρg = -0.376, p = 0.005), suggesting that the same genetic factors underlying risk for type 2 diabetes also influence poor cognitive performance in these domains. Performance in these domains was also associated with type 2 diabetes risk using an endophenotype ranking value approach. Specifically, on measures of attention (CPT d': ß = -0.219, p = 0.005), working memory (digit span backward: ß = -0.326, p = 0.035), and face memory (PFMT: ß = -0.171, p = 0.023; PFMT Delayed: ß = -0.215, p = 0.005), individuals with type 2 diabetes showed the lowest performance, while unaffected/unrelated individuals showed the highest performance, and those related to an individual with type 2 diabetes performed at an intermediate level. CONCLUSIONS/INTERPRETATION: These findings suggest that cognitive impairment may be a useful endophenotype of type 2 diabetes and, therefore, help to elucidate the pathophysiological underpinnings of this chronic disease. DATA AVAILABILITY: The data analysed in this study is available in dbGaP: www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001215.v2.p2.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Adulto , Cognição/fisiologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/fisiopatologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto JovemRESUMO
BACKGROUND: Suicide is major public health concern. It is imperative to find robust biomarkers so that at-risk individuals can be identified in a timely and reliable manner. Previous work suggests mechanistic links between increased cytokines and risk for suicide, but questions remain regarding the etiology of this association, as well as the roles of sex and BMI. METHODS: Analyses were conducted using a randomly-ascertained extended-pedigree sample of 1882 Mexican-American individuals (60% female, mean ageâ¯=â¯42.04, rangeâ¯=â¯18-97). Genetic correlations were calculated using a variance components approach between the cytokines TNF-α, IL-6 and IL-8, and Lifetime Suicide Attempt and Current Suicidal Ideation. The potentially confounding effects of sex and BMI were considered. RESULTS: 159 individuals endorse a Lifetime Suicide Attempt. IL-8 and IL-6 shared significant genetic overlap with risk for suicide attempt (ρgâ¯=â¯0.49, pFDRâ¯=â¯7.67â¯×â¯10-03; ρgâ¯=â¯0.53, pFDRâ¯=â¯0.01), but for IL-6 this was attenuated when BMI was included as a covariate (ρgâ¯=â¯0.37, seâ¯=â¯0.23, pFDRâ¯=â¯0.12). Suicide attempts were significantly more common in females (pFDRâ¯=â¯0.01) and the genetic overlap between IL-8 and risk for suicide attempt was significant in females (ρgâ¯=â¯0.56, pFDRâ¯=â¯0.01), but not in males (ρgâ¯=â¯0.44, pFDRâ¯=â¯0.30). DISCUSSION: These results demonstrate that: IL-8 shares genetic influences with risk for suicide attempt; females drove this effect; and BMI should be considered when assessing the association between IL-6 and suicide. This finding represents a significant advancement in knowledge by demonstrating that cytokine alterations are not simply a secondary manifestation of suicidal behavior, but rather, the pathophysiology of suicide attempts is, at least partly, underpinned by the same biological mechanisms responsible for regulating inflammatory response.
Assuntos
Interleucina-8/genética , Tentativa de Suicídio , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Índice de Massa Corporal , Família , Feminino , Predisposição Genética para Doença , Humanos , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Ideação Suicida , Adulto JovemRESUMO
OBJECTIVES: An interesting consequence of consanguinity is that the inbred singleton becomes informative for genetic variance. We determine the contribution of an inbred singleton to variance component analysis of heritability and linkage. METHODS: Statistical theory for the power of variance component analysis of quantitative traits is used to determine the expected contribution of an inbred singleton to likelihood-ratio tests of heritability and linkage. RESULTS: In variance component models, an inbred singleton contributes relatively little to a test of heritability but can contribute substantively to a test of linkage. For small-to-moderate quantitative trait locus (QTL) effects and a level of inbreeding comparable to matings between first cousins (the preferred form of union in many human populations), an inbred singleton can carry nearly 25% of the information of a non-inbred sib pair. In more highly inbred contexts available with experimental animal populations, nonhuman primate colonies, and some human subpopulations, the contribution of an inbred singleton relative to a sib pair can exceed 50%. CONCLUSIONS: Inbred individuals, even in isolation from other members of a sample, can contribute to variance component estimation and tests of heritability and linkage. Under certain conditions, the informativeness of the inbred singleton can approach that of a non-inbred sib pair.
Assuntos
Consanguinidade , Modelos Genéticos , Ligação Genética , Variação Genética , HumanosRESUMO
The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample (n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for neuroanatomical specificity, 16 specific tracts were additionally considered. We observed negative phenotypic correlations between epigenetic age acceleration and global white matter tract integrity (ρpheno = -0.119, p = 0.028), with evidence of shared genetic (ρgene = -0.463, p = 0.013) but not environmental influences. Negative phenotypic and genetic correlations with age acceleration were also seen for a number of specific white matter tracts, along with additional negative phenotypic correlations between granulocyte abundance and white matter integrity. These findings (i.e., increased acceleration in epigenetic age in peripheral blood correlates with reduced white matter integrity in the brain and shares common genetic influences) provide a window into the neurobiology of aging processes within the brain and a potential biomarker of normal and pathological brain aging.SIGNIFICANCE STATEMENT Epigenetic measures can be used to predict age with a high degree of accuracy and so capture acceleration in biological age, relative to chronological age. The white matter tracts within the brain are also highly sensitive to aging processes. We show that increased biological aging (measured using epigenetic data from blood samples) is correlated with reduced integrity of white matter tracts within the human brain (measured using diffusion tensor imaging) with data from a large sample of Mexican-American families. Given the family design of the sample, we are also able to demonstrate that epigenetic aging and white matter tract integrity also share common genetic influences. Therefore, epigenetic age may be a potential, and accessible, biomarker of brain aging.
Assuntos
Envelhecimento/genética , Imagem de Tensor de Difusão/métodos , Epigênese Genética/genética , Substância Branca/anatomia & histologia , Substância Branca/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Conectoma/métodos , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Adulto JovemRESUMO
Head movements are typically viewed as a nuisance to functional magnetic resonance imaging (fMRI) analysis, and are particularly problematic for resting state fMRI. However, there is growing evidence that head motion is a behavioral trait with neural and genetic underpinnings. Using data from a large randomly ascertained extended pedigree sample of Mexican Americans (n = 689), we modeled the genetic structure of head motion during resting state fMRI and its relation to 48 other demographic and behavioral phenotypes. A replication analysis was performed using data from the Human Connectome Project, which uses an extended twin design (n = 864). In both samples, head motion was significantly heritable (h2 = 0.313 and 0.427, respectively), and phenotypically correlated with numerous traits. The most strongly replicated relationship was between head motion and body mass index, which showed evidence of shared genetic influences in both data sets. These results highlight the need to view head motion in fMRI as a complex neurobehavioral trait correlated with a number of other demographic and behavioral phenotypes. Given this, when examining individual differences in functional connectivity, the confounding of head motion with other traits of interest needs to be taken into consideration alongside the critical important of addressing head motion artifacts.
Assuntos
Índice de Massa Corporal , Movimentos da Cabeça , Imageamento por Ressonância Magnética , Fenótipo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Conectoma , Feminino , Estudos de Associação Genética , Humanos , Padrões de Herança , Masculino , Americanos Mexicanos/genética , Pessoa de Meia-Idade , Descanso , Fatores Sexuais , Adulto JovemRESUMO
Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h2) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10-8). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk.
Assuntos
Doenças Cardiovasculares/genética , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doenças Cardiovasculares/patologia , Feminino , Haplótipos , Humanos , Masculino , Melanesia , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Componente PrincipalRESUMO
Aims: The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Methods and results: Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. Conclusion: We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Aterosclerose/genética , Proteínas de Transporte/genética , HDL-Colesterol/metabolismo , Regulação da Expressão Gênica , Proteínas do Tecido Nervoso/genética , Transportador 1 de Cassete de Ligação de ATP/biossíntese , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Proteínas de Transporte/biossíntese , Linhagem Celular , Colesterol/metabolismo , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Macrófagos/metabolismo , Camundongos Knockout , Proteínas do Tecido Nervoso/biossíntese , RNA/genéticaRESUMO
We searched a gene expression dataset comprised of 634 schizophrenia (SZ) cases and 713 controls for expression outliers (i.e., extreme tails of the distribution of transcript expression values) with SZ cases overrepresented compared with controls. These outlier genes were enriched for brain expression and for genes known to be associated with neurodevelopmental disorders. SZ cases showed higher outlier burden (i.e., total outlier events per subject) than controls for genes within copy number variants (CNVs) associated with SZ or neurodevelopmental disorders. Outlier genes were enriched for CNVs and for rare putative regulatory variants, but this only explained a small proportion of the outlier subjects, highlighting the underlying presence of additional genetic and potentially, epigenetic mechanisms.
Assuntos
Epigênese Genética , Predisposição Genética para Doença , Variação Genética , Esquizofrenia , Transcriptoma , Feminino , Humanos , Masculino , Esquizofrenia/genética , Esquizofrenia/metabolismoRESUMO
Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.
Assuntos
Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Americanos Mexicanos/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Mapeamento Cromossômico , Ilhas de CpG , Metilação de DNA , Diabetes Mellitus Tipo 2/epidemiologia , Epigenômica , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável , Fatores de Risco , Fatores Sexuais , Texas/epidemiologia , Texas/etnologia , Adulto JovemRESUMO
Initial results from sequencing studies suggest that there are relatively few low-frequency (<5%) variants associated with large effects on common phenotypes. We performed low-pass whole-genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: (i) that sequencing would detect single low-frequency-large effect variants that explained similar amounts of phenotypic variance as single common variants, and (ii) that some common variant associations could be explained by low-frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant-common phenotype associations-11 132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11 657 229 high-quality variants of which 6 129 221 and 5 528 008 were common and low frequency (<5%), respectively, low frequency-large effect associations comprised 7% of detectable cis-gene expression traits [89 of 1314 cis-eQTLs at P < 1 × 10(-06) (false discovery rate â¼5%)] and one of eight biomarker associations at P < 8 × 10(-10). Very few (30 of 1232; 2%) common variant associations were fully explained by low-frequency variants. Our data show that whole-genome sequencing can identify low-frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low-frequency variants of large effect.
Assuntos
Estudos de Associação Genética/métodos , Marcadores Genéticos , Fenótipo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Variação Genética , Genoma Humano , Técnicas de Genotipagem , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adulto JovemRESUMO
OBJECTIVES: Individuals with bipolar disorder (BPD) exhibit alterations in their phospholipid levels. It is unclear whether these alterations are a secondary consequence of illness state, or if phospholipids and illness risk overlap genetically. If the latter were true, then phospholipids might provide key insights into the pathophysiology of the illness. Therefore, we rank-ordered phospholipid classes by their genetic overlap with BPD risk in order to establish which class might be most informative in terms of increasing our understanding of illness pathophysiology. METHODS: Analyses were conducted in a sample of 558 individuals, unselected for BPD, from 38 extended pedigrees (average family size=14.79, range=2-82). We calculated a coefficient of relatedness for all family members of nine individuals with BPD in the sample (N=185); this coefficient was set to be zero in unrelated individuals (N=373). Then, under an endophenotype ranking value (ERV) approach, this scalar index was tested against 13 serum-based phospholipid concentrations in order to rank-order lipid classes by their respective overlap with BPD risk. RESULTS: The phosphatidylinositol class was significantly heritable (h2 =0.26, P=6.71 × 10-05 ). It was the top-ranked class, and was significantly associated with BPD risk after correction for multiple testing (ß=-1.18, P=2.10 × 10-03 , ERV=0.49). CONCLUSIONS: We identified a peripheral biomarker, serum-based phosphatidylinositol, which exhibits a significant association with BPD risk. Therefore, given that phosphatidylinositol and BPD risk share partially common etiology, it seems that this lipid class warrants further investigation, not only in terms of treatment, but also as a promising diagnostic and risk marker.
Assuntos
Transtorno Bipolar , Fosfatidilinositóis/sangue , Adulto , Biomarcadores/sangue , Transtorno Bipolar/sangue , Transtorno Bipolar/genética , Endofenótipos/análise , Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Escalas de Graduação Psiquiátrica , Característica Quantitativa Herdável , Fatores de Risco , Espectrometria de Massas em Tandem/métodosRESUMO
Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.
Assuntos
Proteínas ADAM/metabolismo , Síndrome Metabólica/metabolismo , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Resistência à Insulina/imunologia , Resistência à Insulina/fisiologia , Leucócitos Mononucleares/metabolismo , Fígado/metabolismo , Masculino , Síndrome Metabólica/imunologia , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Currently available methods for interrogating DNA-protein interactions at individual genomic loci have significant limitations, and make it difficult to work with unmodified cells or examine single-copy regions without specific antibodies. In this study, we describe a physiological application of the Hybridization Capture of Chromatin-Associated Proteins for Proteomics (HyCCAPP) methodology we have developed. Both novel and known locus-specific DNA-protein interactions were identified at the ENO2 and GAL1 promoter regions of Saccharomyces cerevisiae, and revealed subgroups of proteins present in significantly different levels at the loci in cells grown on glucose versus galactose as the carbon source. Results were validated using chromatin immunoprecipitation. Overall, our analysis demonstrates that HyCCAPP is an effective and flexible technology that does not require specific antibodies nor prior knowledge of locally occurring DNA-protein interactions and can now be used to identify changes in protein interactions at target regions in the genome in response to physiological challenges.
Assuntos
Proteínas de Ligação a DNA/genética , Galactoquinase/genética , Fosfopiruvato Hidratase/genética , Proteômica/métodos , Proteínas de Saccharomyces cerevisiae/genética , Cromatina/genética , Imunoprecipitação da Cromatina/métodos , Regiões Promotoras Genéticas , Ligação Proteica/genética , Saccharomyces cerevisiae/genéticaRESUMO
Schizophrenia is a serious mental illness, involving disruptions in thought and behavior, with a worldwide prevalence of about one percent. Although highly heritable, much of the genetic liability of schizophrenia is yet to be explained. We searched for susceptibility loci in multiplex, multigenerational families affected by schizophrenia, targeting protein-altering variation with in silico predicted functional effects. Exome sequencing was performed on 136 samples from eight European-American families, including 23 individuals diagnosed with schizophrenia or schizoaffective disorder. In total, 11,878 non-synonymous variants from 6,396 genes were tested for their association with schizophrenia spectrum disorders. Pathway enrichment analyses were conducted on gene-based test results, protein-protein interaction (PPI) networks, and epistatic effects. Using a significance threshold of FDR < 0.1, association was detected for rs10941112 (p = 2.1 × 10-5 ; q-value = 0.073) in AMACR, a gene involved in fatty acid metabolism and previously implicated in schizophrenia, with significant cis effects on gene expression (p = 5.5 × 10-4 ), including brain tissue data from the Genotype-Tissue Expression project (minimum p = 6.0 × 10-5 ). A second SNP, rs10378 located in TMEM176A, also shows risk effects in the exome data (p = 2.8 × 10-5 ; q-value = 0.073). PPIs among our top gene-based association results (p < 0.05; n = 359 genes) reveal significant enrichment of genes involved in NCAM-mediated neurite outgrowth (p = 3.0 × 10-5 ), while exome-wide SNP-SNP interaction effects for rs10941112 and rs10378 indicate a potential role for kinase-mediated signaling involved in memory and learning. In conclusion, these association results implicate AMACR and TMEM176A in schizophrenia risk, whose effects may be modulated by genes involved in synaptic plasticity and neurocognitive performance.
Assuntos
Exoma , Marcadores Genéticos , Transtornos Neurocognitivos/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Família , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Transtornos Neurocognitivos/diagnóstico , Transtornos Neurocognitivos/epidemiologia , Fatores de Risco , Esquizofrenia/complicações , Adulto JovemRESUMO
BACKGROUND: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. RESULTS: Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h (2) = 0.50 ± 0.05, p < 4 × 10(-35)), and linkage analysis of serum uric acid concentrations confirmed our previous finding of a novel locus on 3p26 (LOD = 4.9, p < 1 × 10(-5)) in the extended sample. Additionally, we observed strong association of serum uric acid concentrations with variants in following candidate genes in the 3p26 region; inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1), contactin 4 (CNTN4), decapping mRNA 1A (DCP1A); transglutaminase 4 (TGM4) and rho guanine nucleotide exchange factor (GEF) 26 (ARHGEF26) [p < 3 × 10(-7); minor allele frequencies ranged between 0.003 and 0.42] and evidence of cis-regulation for ITPR1 transcripts. CONCLUSION: Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations.
Assuntos
Contactinas/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Americanos Mexicanos/genética , Locos de Características Quantitativas , Ácido Úrico/sangue , Adulto , Cromossomos Humanos Par 3 , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10(-7)) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations.
Assuntos
Doenças Cardiovasculares/genética , Mapeamento Cromossômico , Expressão Gênica , Locos de Características Quantitativas , Doenças Cardiovasculares/metabolismo , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Melanesia , Fenótipo , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas , Característica Quantitativa Herdável , Fatores de Risco , Transcrição GênicaRESUMO
Previous work has shown that the hippocampus is smaller in the brains of individuals suffering from major depressive disorder (MDD) than those of healthy controls. Moreover, right hippocampal volume specifically has been found to predict the probability of subsequent depressive episodes. This study explored the utility of right hippocampal volume as an endophenotype of recurrent MDD (rMDD). We observed a significant genetic correlation between the two traits in a large sample of Mexican American individuals from extended pedigrees (ρg = -0.34, p = 0.013). A bivariate linkage scan revealed a significant pleiotropic quantitative trait locus on chromosome 18p11.31-32 (LOD = 3.61). Bivariate association analysis conducted under the linkage peak revealed a variant (rs574972) within an intron of the gene SMCHD1 meeting the corrected significance level (χ(2) = 19.0, p = 7.4 × 10(-5)). Univariate association analyses of each phenotype separately revealed that the same variant was significant for right hippocampal volume alone, and also revealed a suggestively significant variant (rs12455524) within the gene DLGAP1 for rMDD alone. The results implicate right-hemisphere hippocampal volume as a possible endophenotype of rMDD, and in so doing highlight a potential gene of interest for rMDD risk.
Assuntos
Proteínas Cromossômicas não Histona/genética , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Hipocampo/patologia , Mutação/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Endofenótipos , Saúde da Família , Feminino , Lateralidade Funcional/genética , Ligação Genética , Predisposição Genética para Doença , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Americanos Mexicanos , Pessoa de Meia-Idade , Recidiva , Proteínas Associadas SAP90-PSD95 , Adulto JovemRESUMO
BACKGROUND: Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS). OBJECTIVE: We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk. METHODS: We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size (Neff) = 5555) and a large MS GWAS (Neff = 15,231). RESULTS: We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 (p = 4.11 × 10-9). A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP (p = 3.32 × 10-20). By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance (p < 5 × 10-8). CONCLUSIONS: Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.